Cytosolic phospholipase A2α and peroxisome proliferator-activated receptor γ signaling pathway counteracts transforming growth factor β–mediated inhibition of primary and transformed hepatocyte growth

Authors

  • Chang Han,

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
    2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    • Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-79, New Orleans, LA 70112
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  • William C. Bowen,

    1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Guiying Li,

    1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    2. Key Laboratory for Molecular Enzymology and Engineering of Ministry of Education, Jilin University, Changchun, China
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  • Anthony J. Demetris,

    1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • George K. Michalopoulos,

    1. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
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  • Tong Wu

    Corresponding author
    1. Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA
    2. Department of Pathology, University of Pittsburgh School of Medicine, Pittsburgh, PA
    • Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, 1430 Tulane Avenue, SL-79, New Orleans, LA 70112
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    • fax: 504-988-7862


  • Potential conflict of interest: Dr. Demetris is a consultant for Wyeth, Novartis, and Bristol-Myers Squibb.

Abstract

Hepatocellular carcinoma often develops in the setting of abnormal hepatocyte growth associated with chronic hepatitis and liver cirrhosis. Transforming growth factor β (TGF-β) is a multifunctional cytokine pivotal in the regulation of hepatic cell growth, differentiation, migration, extracellular matrix production, stem cell homeostasis, and hepatocarcinogenesis. However, the mechanisms by which TGF-β influences hepatic cell functions remain incompletely defined. We report herein that TGF-β regulates the growth of primary and transformed hepatocytes through concurrent activation of Smad and phosphorylation of cytosolic phospholipase A2α (cPLA2α), a rate-limiting key enzyme that releases arachidonic acid for the production of bioactive eicosanoids. The interplays between TGF-β and cPLA2α signaling pathways were examined in rat primary hepatocytes, human hepatocellular carcinoma cells, and hepatocytes isolated from newly developed cPLA2α transgenic mice. Conclusion: Our data show that cPLA2α activates peroxisome proliferator-activated receptor γ (PPAR-γ) and thus counteracts Smad2/3-mediated inhibition of cell growth. Therefore, regulation of TGF-β signaling by cPLA2α and PPAR-γ may represent an important mechanism for control of hepatic cell growth and hepatocarcinogenesis. (HEPATOLOGY 2010;)

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